Deletion of the human T-cell receptor δ-gene by a site-specific recombination

Abstract

The newly described T-eell receptor (TCR) δ locus^1–5 is located inside the TCR α locus, between variable region (V)α and joining region (J)α^6,7. Although the δ and α TCR genes are physically linked on the same chromosome, they are sequentially expressed during T-cell development⁸. This implies the existence of a highly efficient regulatory mechanism by which these two genes are independently rearranged. We have recently described⁹ a genetic element 'T early α (TEA) in humans transcribed in foetal thymocytes, spliced alternatively to constant region (C)α, and located between the TCR- δ locus (5') and the group of Jα segments (3′). Importantly, TEA flanks a common site of rearrangement in the thymus, and distinguishes cells using TCR-γ/δ (TEA in germline configuration) from cells using TCR-α/β (TEA deleted on both chromosomes). In order to understand this TEA-associated recombination we analysed genomic clones representing these thymic rearrangements. We show that the TEA-associated recombination deletes the δ locus before productive (VδDδJδ) rearrangement. The diversity (D)δ and Jδ regions, which provide the major source of δ gene diversity, are eliminated as a consequence of δ gene deletion and cannot then be used in conjunction with an α-TCR. We propose that the TEA-associated deletion of TCR–δ precedes the formation of an α-TCR and could down-regulate TCR–δ formation in maturing thymus.